Cerebral Metabolic Signature of Chronic Benzodiazepine Use in Nondemented Older Adults: An FDG-PET Study in the MEMENTO Cohort.

OBJECTIVE: We sought to examine the association between chronic Benzodiazepine (BZD) use and brain metabolism obtained from 2-deoxy-2-fluoro-D-glucose (FDG) positron emission tomography (PET) in the MEMENTO clinical cohort of nondemented older adults with an isolated memory complaint or mild cognitive impairment at baseline. METHODS: Our analysis focused on 3 levels: (1) the global mean brain standardized uptake value (SUVR), (2) the Alzheimer's disease (AD)-specific regions of interest (ROIs), and (3) the ratio of total SUVR on the brain and different anatomical ROIs. Cerebral metabolism was obtained from 2-deoxy-2-fluoro-D-glucose-FDG-PET and compared between chronic BZD users and nonusers using multiple linear regressions adjusted for age, sex, education, APOE ε 4 copy number, cognitive and neuropsychiatric assessments, history of major depressive episodes and antidepressant use. RESULTS: We found that the SUVR was significantly higher in chronic BZD users (n = 192) than in nonusers (n = 1,122) in the whole brain (beta = 0.03; p = 0.038) and in the right amygdala (beta = 0.32; p = 0.012). Trends were observed for the half-lives of BZDs (short- and long-acting BZDs) (p = 0.051) and Z-drug hypnotic treatments (p = 0.060) on the SUVR of the right amygdala. We found no significant association in the other ROIs. CONCLUSION: Our study is the first to find a greater global metabolism in chronic BZD users and a specific greater metabolism in the right amygdala. Because the acute administration of BZDs tends to reduce brain metabolism, these findings may correspond to a compensatory mechanism while the brain adapts with global metabolism upregulation, with a specific focus on the right amygdala.

Dynamic CZT-SPECT: Characterizing the Lower Values of Myocardial Blood Flow and Reserve.

ABSTRACT: CZT-SPECT myocardial perfusion enables quantification of myocardial blood flow (MBF). Normal values and thresholds have been accurately defined in PET but remain unclear in SPECT. The aim of this study was to report normal MBF and myocardial flow reserve values in very low-risk patients referred for coronary artery disease screening with dynamic SPECT, in comparison with patients experiencing coronary artery disease. Eighty-four patients (31 male) were analyzed. The mean 10 years risk of fatal cardiovascular events score was 2.7% ± 1.4%. The mean global stress MBF and myocardial flow reserve were 1.6 ± 0.6 mL/min/g and 2.7 ± 0.7.

Metabotropic Glutamate Receptor Subtype 5 Positron-Emission-Tomography Radioligands as a Tool for Central Nervous System Drug Development: Between Progress and Setbacks.

The metabotropic glutamate receptor subtype 5 (mGluR5) is a class C G-protein-coupled receptor (GPCR) that has been implicated in various neuronal processes and, consequently, in several neuropsychiatric or neurodevelopmental disorders. Over the past few decades, mGluR5 has become a major focus for pharmaceutical companies, as an attractive target for drug development, particularly through the therapeutic potential of its modulators. In particular, allosteric binding sites have been targeted for better specificity and efficacy. In this context, Positron Emission Tomography (PET) appears as a useful tool for making decisions along a drug candidate's development process, saving time and money. Thus, PET provides quantitative information about a potential drug candidate and its target at the molecular level. However, in this area, particular attention has to be given to the interpretation of the PET signal and its conclusions. Indeed, the complex pharmacology of both mGluR5 and radioligands, allosterism, the influence of endogenous glutamate and the choice of pharmacokinetic model are all factors that may influence the PET signal. This review focuses on mGluR5 PET radioligands used at several stages of central nervous system drug development, highlighting advances and setbacks related to the complex pharmacology of these radiotracers.

Precision of Myocardial Blood Flow and Flow Reserve Measurement During CZT SPECT Perfusion Imaging Processing: Intra- and Interobserver Variability.

The aim of this study was to evaluate the reproducibility of myocardial blood flow (MBF) and myocardial flow reserve (MFR) measurement in patients referred for dynamic SPECT. Methods: We retrospectively analyzed patients referred for myocardial perfusion imaging. SPECT data were acquired on a cadmium zinc telluride-based pinhole cardiac camera in list mode using a stress (251 ± 15 MBq)/rest (512 ± 26 MBq) 1-d 99mTc-tetrofosmin protocol. Kinetic analyses were done with software using a 1-tissue-compartment model and converted to MBF using a previously determined extraction fraction correction. MFR was analyzed and compared globally and regionally. Motion detection was applied, but not attenuation correction. Results: In total, 124 patients (64 male, 60 female) were included, and SPECT acquisitions were twice reconstructed by the same nuclear medicine board-certified physician for 50 patients and by 2 different physicians for 74. Both intra- and interobserver measurements of global MFR had no significant bias (-0.01 [P = 0.94] and 0.01 [P = 0.67], respectively). However, rest MBF and stress MBF were significantly different in global left ventricular evaluation (P = 0.001 and P = 0.002, respectively) and in the anterior territory (P < 0.0001) on interuser analysis. The average coefficient of variation was 15%-30% of the mean stress MBF if the analysis was performed by the same physician or 2 different physicians and was around 20% of the mean MFR independently of the processing physician. Using the MFR threshold of 2, we noticed good intrauser agreement, whereas it was moderate when the users were different (κ = 0.75 [95% CI, 0.56-0.94] vs. 0.56 [95% CI, 0.36-0.75], respectively). Conclusion: Repeated measurements of global MFR by the same physician or 2 different physicians were similar, with an average coefficient of variation of 20%. Better reproducibility was achieved for intrauser MBF evaluation. Automation of processing is needed to improve reproducibility.

Glutamatergic synapse in autism: a complex story for a complex disorder.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder whose pathophysiological mechanisms are still unclear. Hypotheses suggest a role for glutamate dysfunctions in ASD development, but clinical studies investigating brain and peripheral glutamate levels showed heterogenous results leading to hypo- and hyper-glutamatergic hypotheses of ASD. Recently, studies proposed the implication of elevated mGluR5 densities in brain areas in the pathophysiology of ASD. Thus, our objective was to characterize glutamate dysfunctions in adult subjects with ASD by quantifying (1) glutamate levels in the cingulate cortex and periphery using proton magnetic resonance spectroscopy and metabolomics, and (2) mGluR5 brain density in this population and in a validated animal model of ASD (prenatal exposure to valproate) at developmental stages corresponding to childhood and adolescence in humans using positron emission tomography. No modifications in cingulate Glu levels were observed between individuals with ASD and controls further supporting the difficulty to evaluate modifications in excitatory transmission using spectroscopy in this population, and the complexity of its glutamate-related changes. Our imaging results showed an overall increased density in mGluR5 in adults with ASD, that was only observed mostly subcortically in adolescent male rats prenatally exposed to valproic acid, and not detected in the stage corresponding to childhood in the same animals. This suggest that clinical changes in mGluR5 density could reflect the adaptation of the glutamatergic dysfunctions occurring earlier rather than being key to the pathophysiology of ASD.

Metastatic Castration-Resistant Prostate Cancer with BRCA2 Mutation: The Challenge Incorporating PARP Inhibitors and Platinum in Treatment Sequencing.

Prostate cancer is the second most frequent malignancy in men worldwide. Despite the improvement in survival achieved by increasingly early diagnosis and advances in treatment, it is still associated with high mortality. Because of its molecular heterogeneity, there is a need to identify genetic alterations in order to apply targeted therapies. Increasing evidence suggests that the PARP inhibitor olaparib could have a significant synthetic lethal effect in prostate cancer with homologous recombination defects, such as BRCA1/2 mutations. It is not yet known if, under these circumstances, platinum-based chemotherapy induces higher response rates in prostate cancer. We present the case of a patient with BRCA2-mutated metastatic castration-resistant prostate cancer whose treatment sequence included carboplatin and olaparib. LEARNING POINTS: Metastatic castration-resistant prostate cancer (mCRPC) remains a lethal disease despite significant progress in treatment.The BRCA2 mutation is associated with worse survival and so timely genetic screening is important.Studies are needed to identify the best therapeutic sequencing strategy for mCRPC harbouring homologous recombination repair defects, which includes PARP inhibitors and platinum.

Neuroinflammation PET imaging of the translocator protein (TSPO) in Alzheimer's disease: An update.

Neuroinflammation is a significant contributor to Alzheimer's disease (AD). Until now, PET imaging of the translocator protein (TSPO) has been widely used to depict the neuroimmune endophenotype of AD. The aim of this review was to provide an update to the results from 2018 and to advance the characterization of the biological basis of TSPO imaging in AD by re-examining TSPO function and expression and the methodological aspects of interest. Although the biological basis of the TSPO PET signal is obviously related to microglia and astrocytes in AD, the observed process remains uncertain and might not be directly related to neuroinflammation. Further studies are required to re-examine the cellular significance underlying a variation in the PET signal in AD.

Benzodiazepine use and neuroimaging markers of Alzheimer's disease in nondemented older individuals: an MRI and 18F Florbetapir PET study in the MEMENTO cohort.

Recent evidence suggests an association between benzodiazepines (BZDs) use and lower brain amyloid load, a hallmark of AD pathophysiology. Other AD-related markers include hippocampal atrophy, but the effect of BZDs on hippocampal volume remains unclear. We aimed at 1) replicating findings on BZDs use and brain amyloid load and 2) investigating associations between BZDs use and hippocampal volume, in the MEMENTO clinical cohort of nondemented older adults with isolated memory complaint or light cognitive impairment at baseline. Total Standardized Uptake Value Ratio (SUVR) of brain amyloid load and hippocampal volume (HV) were obtained, respectively, from 18F Florbetapir positron emission tomography (PET) and magnetic resonance imaging (MRI), and compared between BZD chronic users and nonusers using multiple linear regressions adjusted for age, sex, educational level, ApoE ε4 genotype, cognitive and neuropsychiatric assessments, history of major depressive episodes and antidepressant intake. BZD users were more likely to manifest symptoms of depression, anxiety and apathy. In the MRI subgroup, BZD users were also more frequently females with low education and greater clinical impairments as assessed with the clinical dementia rating scale. Short- versus long-acting BZDs, Z-drugs versus non-Z-drugs BZDs, as well as dose and duration of BZD use, were also considered in the analyses. Total SUVR and HV were significantly lower and larger, respectively, in BZD users (n = 38 in the PET subgroup and n = 331 in the MRI subgroup) than in nonusers (n = 251 in the PET subgroup and n = 1840 in the MRI subgroup), with a medium (Cohen's d = -0.43) and low (Cohen's d = 0.10) effect size, respectively. Short-acting BZDs and Z-drugs were more significantly associated with larger HV. We found no effect of dose and duration of BZD use. Our results support the involvement of the GABAergic system as a potential target for blocking AD-related pathophysiology, possibly via reduction in neuronal activity and neuroinflammation. Future longitudinal studies may confirm the causal effect of BZDs to block amyloid accumulation and hippocampal atrophy.

Imaging of dopamine transporter with [18F]LBT-999: initial evaluation in healthy volunteers.

BACKGROUND: The aim of this study was to evaluate in healthy human brain the distribution, uptake, and kinetics of [18F]LBT-999, a PET ligand targeting the dopamine transporter, to assess its ability to explore dopaminergic innervation, using a shorter protocol, more convenient for patients than currently with [123I]ioflupane. METHODS: After intravenous injection of [18F]LBT-999, 8 healthy subjects (53-80y) underwent a dynamic PET-scan. Venous samples were concomitantly obtained for metabolites analysis. Time activity curves (TACs) were generated for several ROIs (caudate, putamen, occipital cortex, substantia nigra and cerebellum). Cerebellum was used as reference region to calculate binding potentials (BPND). RESULTS: No adverse events or detectable pharmacological effects were reported. [18F]LBT-999 PET revealed a good cerebral distribution, with an intense and symmetric uptake in both putamen and caudate (BPND of 6.75±1.17 and 6.30±1.17, respectively), without other brain abnormal tracer accumulation. Regional TACs showed a plateau from the maximal uptake, 20min pi, to the end of the acquisition for both caudate and putamen, whereas uptake in substantia nigra decreased progressively. A faster clearance and lowest BPND values were observed in both cortex and cerebellum. Ratios to the cerebellum exhibit value of about 3 in substantia nigra, close to 10 for both caudate and putamen, and remained around the value of 1 in cortex. The parent fraction of [18F]LBT-999 in plasma was 80%, 60% and 45% at 15, 30 and 45 min pi, respectively. CONCLUSIONS: These findings support the usefulness of [18F]LBT-999 for a quantitative clinical evaluation of presynaptic dopaminergic innervation.

Regadenoson versus dipyridamole: Evaluation of stress myocardial blood flow response on a CZT-SPECT camera.

BACKGROUND: Regadenoson is a selective adenosine receptor agonist. It is currently unclear if the level of hyperemia differs between stress agents. We compared Myocardial Blood Flow (MBF) and Myocardial Flow Reserve (MFR) response on CZT-SPECT Myocardial Perfusion Imaging (MPI) to evaluate if dipyridamole and regadenoson could induce the same level of hyperemia. METHODS: 228 patients with dynamic CZT-SPECT MPI were retrospectively analyzed (66 patients stressed with regadenoson and 162 with dipyridamole) in terms of MBF and MFR. To rule out confounding factors, two groups of 41 patients were matched for clinical characteristics in a sub-analysis, excluding high cardiovascular risk patients. RESULTS: Overall stress MBF was higher in regadenoson patients (1.71 ± 0.73 vs. 1.44 ± 0.55 mL·min-1·g-1 for regadenoson and dipyridamole, respectively, p < .05). However, when confounding factors were ruled out, stress MBF (1.57 ± 0.56 vs. 1.61 ± 0.62 mL·min-1·g-1 for dipyridamole and regadenoson, respectively, p = .88) and MFR (2.62 ± 0.77 vs. 2.46 ± 0.76 for dipyridamole and regadenoson, respectively, p = .40) were not different between regadenoson and dipyridamole. CONCLUSIONS: Our results suggest that dipyridamole and regadenoson induce equivalent hyperemia in dynamic SPECT with similar stress MBF and MFR in comparable patients.

Combining flow and reserve measurement during myocardial perfusion imaging: A new era for myocardial perfusion scintigraphy?

Myocardial flow reserve represents the ratio of myocardial blood flow between stress and rest, giving functional information about both macrocirculation and microcirculation; it has been reported extensively in positron emission tomography, with an increase in diagnostic performance, providing important prognostic information and being a powerful tool to guide therapy. Advances in single photon emission computed tomography, with the widespread availability of "cadmium zinc telluride" single photon emission computed tomography cameras, raise the question of myocardial flow reserve use in daily clinical practice. In this article, we review the pathophysiology of myocardial blood flow and myocardial flow reserve, and the initial data available from single photon emission computed tomography myocardial blood flow and myocardial flow reserve evaluation; we also discuss potential limitations to the wider implementation of flow evaluation in single photon emission computed tomography.

Single Photon Emission Computed Tomography/Positron Emission Tomography Molecular Imaging for Parkinsonism: A Fast-Developing Field.

The early differential diagnosis of Parkinson disease and atypical parkinsonism is a major challenge. The use of single photon emission computed tomography (SPECT)/positron emission tomography (PET) molecular imaging to investigate parkinsonism is a fast-developing field. Imaging biomarker research may potentially lead to more accurate disease detection, enabling earlier diagnosis and treatment. This review summarizes recent SPECT/PET advances in radiopharmaceuticals and imaging technologies/analyses that improve the diagnosis of neurodegenerative parkinsonism. We are currently witnessing a turning point in the field. Integrating molecular imaging as a diagnostic technique represents an opportunity to reassess the strategies for diagnosing neurodegenerative parkinsonism. ANN NEUROL 2021;90:711-719.

Myocardial Flow Reserve Measurement During CZT-SPECT Perfusion Imaging for Coronary Artery Disease Screening: Correlation With Clinical Findings and Invasive Coronary Angiography-The CFR-OR Study.

Purpose: The aim of this study was to assess the results of cadmium zinc telluride (CZT)- single-photon emission computed tomography (SPECT) myocardial flow reserve (MFR) in coronary artery disease (CAD) screening regarding clinical risk and its correlation to invasive coronary angiography (ICA). Methods: A total of 137 patients (61 male and 76 female) referred for CAD screening myocardial perfusion imaging (MPI) between November 2018 and April 2020 were included in the CFR-OR prospective trial. The 10-year risk of cardiovascular death according to the European Society of Cardiology (SCORE) was calculated. SPECT 1-day 99mTc-tetrofosmin protocol was acquired on CZT cardiac-dedicated pinhole cameras. Low-dose thoracic CT was used for coronary calcium score (CCS) evaluation. ICA, when performed within 3 months, was also analyzed. Results: Mean SCORE and mean global MFR were, respectively, 4 ± 3.1% and 2.50 ± 0.74; 34 patients had impaired CFR (using a threshold of 2). There was a significant inverse correlation between MFR and SCORE (p = 0.006), gender (p = 0.019), and number of cardiovascular risk factors (p = 0.01). MFR was significantly reduced in patients with CCS above 1 (p = 0.01). No significant correlation was found between MFR and individual cardiovascular risk factors (dyslipidemia, hypertension, diabetes, or family history of CAD). A total of 23 patients underwent ICA. Global MFR SPECT sensitivity and specificity were 83.3 and 100 %, respectively, with an area under the curve of 0.94. Conclusion: Adding MFR to SPECT MPI for CAD screening on CZT camera may contribute to high-risk patient identification and enhance diagnostic performances. MFR could help physician decision to perform ICA.

Impact of attenuation correction for CZT-SPECT measurement of myocardial blood flow.

OBJECTIVES: Most of cardiac dedicated CZT-SPECT systems are not equipped with CT, whereas PET systems are. We evaluated the impact of AC correction on CZT-SPECT myocardial blood flow (MBF) and myocardial flow reserve (MFR) measurements. METHODS: 104 patients were included. SPECT data were acquired on cadmium zinc telluride (CZT)-based pinhole cardiac camera in listmode using a stress (250 ± 17 MBq)/rest (511 ± 23 MBq) 1-day Tc-99m-tetrofosmin protocol. Low-dose CT was acquired on another SPECT/CT camera in the same position. All analysis was performed using Corridor4DM. RESULTS: Stress and rest MBF were significantly lower when AC was applied (P < 0.001). For regional and global MFR, there was no significant difference between AC and NAC measurements (P > 0.25 at least). Mean global LV MFR was 2.43 ± 0.87 and 2.33 ± 0.89, respectively, for NAC and AC measurements. Using a threshold of 2, 86 patients (83%) remained classified as normal and abnormal regarding global LV MFR whether AC was applied or not. Mean difference between NAC and AC values for the 18 other patients was 0.3. CONCLUSION: AC correction does not significantly affect MFR measurement both in regional and global LV analyses.

Altered Biodistribution of 68Ga-DOTATOC.

ABSTRACT: 68Ga-DOTATOC PET/CT of a patient with metastatic neuroendocrine tumor reveals an abnormal biodistribution of the tracer with a vascular binding and a very low fixation on the known lesions despite the temporary discontinuation of "cold" somatostatin analogs. A possible interaction with a high intake of turmeric may be suspected by inhibition of hepatic uptake process.

Rare Bronchial Tumour and an Emergent Surgery Due to Uncontrollable Haemorrhage / Tumor bronquial infrecuente y cirugía de emergencia por hemorragia incontrolable

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Usefulness of PET With [18F]LBT-999 for the Evaluation of Presynaptic Dopaminergic Neuronal Loss in a Clinical Environment.

Purpose: The density of the neuronal dopamine transporter (DAT) is directly correlated with the presynaptic dopaminergic system injury. In a first study, we evaluated the brain distribution and kinetics of [18F]LBT-999, a DAT PET radioligand, in a group of eight healthy subjects. Taking into account the results obtained in healthy volunteers, we wanted to evaluate whether the loss of presynaptic striatal dopaminergic fibers could be estimated, under routine clinical conditions, using [18F]LBT-999 and a short PET acquisition. Materials and methods: Six patients with Parkinson's disease (PD) were compared with eight controls. Eighty-nine minutes of dynamic PET following an intravenous injection of [18F]LBT-999 were acquired. Using regions of interest for striatal nuclei, substantia nigra (SN), cerebellum, and occipital cortex, defined over each T1 3D MRI, time-activity curves (TACs) were obtained. From TACs, binding potential (BPND) using the simplified reference tissue model and distribution volume ratios (DVRs) using Logan graphical analysis were calculated. Ratios obtained for a 10-min image, acquired between 30 and 40 min post-injection, were also calculated. Cerebellum activity was used as non-specific reference region. Results: In PD patients and as expected, striatal uptake was lower than in controls which is confirmed by BPND, DVR, and ratios calculated for both striatal nuclei and SN, significantly inferior in PD patients compared with controls (p < 0.001). Conclusions: PET with [18F]LBT-999 could be an alternative to assess dopaminergic presynaptic injury in a clinical environment using a single 10 min acquisition.

Faster Acquisition for Dopamine Transporter Imaging Using Swiftscan Step and Shoot Continuous SPECT Without Impairing Visual and Semiquantitative Analysis.

Aim: Dopamine transporter (DAT) imaging with [123I] FP-CIT (DaTSCAN) is an established diagnostic tool in parkinsonism and dementia. Using a low energy high resolution and sensitivity (LEHRS) collimator and step and shoot continuous scanning mode, Swiftscan single photon emission computed tomography (SPECT) (GE Healthcare) enhances sensitivity and enables time or dose reduction. In this phantom and clinical study, we aim to validate a 25% reduction of the acquisition time using Swiftscan and its lack of effect on visual or quantitative analysis. Methods: Anthropomorphic striatal phantom with fillable striata was used. SPECT data from 30 normals (12 men, 18 women; age range, 39-91 years; mean, 71 years ± 11) and 30 patients with Parkinson disease or other neurodegenerative disease with extra-pyramidal syndrome (16 men, 14 women; age range, 43-84 years; mean, 69 years ± 10) were also included. Both phantom and clinical data were acquired using Swiftscan and reconstructed with full-time and 25%-time reduction. Striatal binding ratios (SBRs) were calculated using DaTQUANT software. Results: Both in phantom experiments and in clinical cases, visual analysis remained stable and SBRs were not significantly different whether using Swiftscan or Swiftscan with 25%-time reduction (p < 0.001). There was an excellent inter-rater agreement and no effect of time reduction on diagnosis or on image quality. Conclusion: Using Swiftscan step and shoot continuous SPECT mode, 25%-time reduction can be applied to DaTSCAN acquisition protocols, without impairing visual or quantitative analysis.

Pretreatment 18F-FDG PET/CT Radiomics Predict Local Recurrence in Patients Treated with Stereotactic Body Radiotherapy for Early-Stage Non-Small Cell Lung Cancer: A Multicentric Study.

The aim of this retrospective multicentric study was to develop and evaluate a prognostic 18F-FDG PET/CT radiomic signature in early-stage non-small cell lung cancer patients treated with stereotactic body radiotherapy (SBRT). Methods: Patients from 3 different centers (n = 27, 29, and 8) were pooled to constitute the training set, whereas the patients from a fourth center (n = 23) were used as the testing set. The primary endpoint was local control. The primary tumor was semiautomatically delineated in the PET images using the fuzzy locally adaptive Bayesian algorithm, and manually in the low-dose CT images. In total, 184 Image Biomarkers Standardization Initiative-compliant radiomic features were extracted. Seven clinical and treatment parameters were included. We used ComBat to harmonize radiomic features extracted from the 4 institutions relying on different PET/CT scanners. In the training set, variables found significant in the univariate analysis were fed into a multivariate regression model, and models were built by combining independent prognostic factors. Results: Median follow-up was 21.1 mo (range, 1.7-63.4 mo) and 25.5 mo (range, 7.7-57.8 mo) in training and testing sets, respectively. In univariate analysis, none of the clinical variables, 2 PET features, and 2 CT features were significantly predictive of local control. The best predictive models in the training set were obtained by combining one feature from PET (Information Correlation 2) and one feature from CT (flatness), reaching a sensitivity of 100% and a specificity of 96%. Another model combining 2 PET features (Information Correlation 2 and strength) reached sensitivity of 100% and specificity of 88%, both with an undefined hazard ratio (P < 0.001). The latter model obtained an accuracy of 0.91 (sensitivity, 100%; specificity, 81%), with a hazard ratio undefined (P = 0.023) in the testing set; however, other models relying on CT radiomic features only or the combination of PET and CT features failed to validate in the testing set. Conclusion: We showed that 2 radiomic features derived from 18F-FDG PET were independently associated with local control in patients with non-small cell lung cancer undergoing SBRT and could be combined in an accurate predictive model. This model could provide local relapse-related information and could be helpful in clinical decision making.